Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel

Ilani, Niloufar; Armanious, Nancy; Lue, Yanhe; Swerdloff, Ronald S.; Baravarian, Sima; Adler, A. A.; Tsang, Christina; Jia, Yongyi; Cui, Yugui; Wang, Xinghai; Zhou, Zuomin; Sha, Jiahao; Wang, Christina

doi:10.1093/humrep/des340

Cited by 19 publications

(8 citation statements)

References 37 publications

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“…This latter effect can probably be attributed to claudin-5, which is also found between neighboring cells ( Fig 6E ). Claudin-3, which is known to be associated with newly formed tight junctions only [ 14 , 60 ], is evenly distributed over the entire cell and therefore probably does not contribute to the increased TER. Although claudin expression has been shown to be regulated by androgens [ 14 ], the classical AR does not seem to be involved in the signaling events that lead to increased expression of claudin-3 and -5, since abrogation of its expression does not affect the stimulatory effect of DHEAS ( Fig 7 ).…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnα11-Coupled Receptor in Sertoli Cells

et al. 2016

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Dehydroepiandrosterone sulfate (DHEAS) is a circulating sulfated steroid considered to be a pro-androgen in mammalian physiology. Here we show that at a physiological concentration (1 μM), DHEAS induces the phosphorylation of the kinase Erk1/2 and of the transcription factors CREB and ATF-1 in the murine Sertoli cell line TM4. This signaling cascade stimulates the expression of the tight junction (TJ) proteins claudin-3 and claudin-5. As a consequence of the increased expression, tight junction connections between neighboring Sertoli cells are augmented, as demonstrated by measurements of transepithelial resistance. Phosphorylation of Erk1/2, CREB, or ATF-1 is not affected by the presence of the steroid sulfatase inhibitor STX64. Erk1/2 phosphorylation was not observed when dehydroepiandrosterone (DHEA) was used instead of DHEAS. Abrogation of androgen receptor (AR) expression by siRNA did not affect DHEAS-stimulated Erk1/2 phosphorylation, nor did it change DHEAS-induced stimulation of claudin-3 and claudin-5 expression. All of the above indicate that desulfation and conversion of DHEAS into a different steroid hormone is not required to trigger the DHEAS-induced signaling cascade. All activating effects of DHEAS, however, are abolished when the expression of the G-protein Gnα11 is suppressed by siRNA, including claudin-3 and -5 expression and TJ formation between neighboring Sertoli cells as indicated by reduced transepithelial resistance. Taken together, these results are consistent with the effects of DHEAS being mediated through a membrane-bound G-protein-coupled receptor interacting with Gnα11 in a signaling pathway that resembles the non-classical signaling pathways of steroid hormones. Considering the fact that DHEAS is produced in reproductive organs, these findings also suggest that DHEAS, by acting as an autonomous steroid hormone and influencing the formation and dynamics of the TJ at the blood-testis barrier, might play a crucial role for the regulation and maintenance of male fertility.

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Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnα11-Coupled Receptor in Sertoli Cells

et al. 2016

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“…2): Claudin 3, a molecule expressed in a wide variety of different epithelia4059, was found to be an essential component in the blood-brain60 as well as the blood-testis barrier61. In that context, Claudin 3 was characterized as a strong paracellular barrier molecule for charged and uncharged molecules and its overexpression resulted in a significant increase in number and complexity of TJ sealing strands19.…”

Section: Discussionmentioning

confidence: 99%

Claudin expression in the rat endolymphatic duct and sac - first insights into regulation of the paracellular barrier by vasopressin

Runggaldier

Pradas

Neckel

et al. 2017

Sci Rep

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Hearing and balance functions of the inner ear rely on the homeostasis of the endolymphatic fluid. When disturbed, pathologic endolymphatic hydrops evolves as observed in Menière’s disease. The molecular basis of inner ear fluid regulation across the endolymphatic epithelium is largely unknown. In this study we identified the specific expression of the tight junction (TJ) molecules Claudin 3, 4, 6, 7, 8, 10, and 16 in epithelial preparations of the rat inner ear endolymphatic duct (ED) and endolymphatic sac (ES) by high-throughput qPCR and immunofluorescence confocal microscopy. Further we showed that Claudin 4 in the ES is a target of arginine-vasopressin (AVP), a hormone elevated in Menière’s disease. Moreover, our transmission-electron microscopy (TEM) analysis revealed that the TJs of the ED were shallow and shorter compared to the TJ of the ES indicating facilitation of a paracellular fluid transport across the ED epithelium. The significant differences in the subcellular localization of the barrier-forming protein Claudin 3 between the ED and ES epithelium further support the TEM observations. Our results indicate a high relevance of Claudin 3 and Claudin 4 as important paracellular barrier molecules in the ED and ES epithelium with potential involvement in the pathophysiology of Menière’s disease.

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“… 3 4 6 33 While functional tests of the human Sertoli cell TJ in vivo with tracers is not currently feasible to our knowledge, claudin-11 staining was seen to be normal in gonadotropin suppressed men after 9 weeks despite the postmeiotic germ cell numbers reduced to 40% of control. 34 The absence of anti-sperm antibodies suggested that the Sertoli cell TJ was functional. As mentioned earlier, however, men with non-gonadotropin derived testicular disorders do present with claudin-11 redistribution.…”

Section: Discussionmentioning

confidence: 99%

Claudin-11 and occludin are major contributors to Sertoli cell tight junction function, in vitro

et al. 2016

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The Sertoli cell tight junction (TJ) is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% (P < 0.01), 51% (P < 0.01), and 62% (P < 0.01), respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli cell TJ. We provide quantitative evidence that claudin-11 contributes significantly (P < 0.01) to Sertoli cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant (P < 0.01) contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function.

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Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel

Cited by 19 publications

References 37 publications

Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnα11-Coupled Receptor in Sertoli Cells

Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnα11-Coupled Receptor in Sertoli Cells

Claudin expression in the rat endolymphatic duct and sac - first insights into regulation of the paracellular barrier by vasopressin

Claudin-11 and occludin are major contributors to Sertoli cell tight junction function, in vitro

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